Characterization of Ebola Virus Disease (EVD) in Rhesus Monkeys for Development of EVD Therapeutics

Abstract

Recent Ebola virus (EBOV) outbreaks in West Africa and the Democratic Republic of the Congo have highlighted the urgent need for approval of medical countermeasures for treatment and prevention of EBOV disease (EVD). Until recently, when successes were achieved in characterizing the efficacy of multiple experimental EVD therapeutics in humans, the only feasible way to obtain data regarding potential clinical benefits of candidate therapeutics was by conducting well-controlled animal studies. Nonclinical studies are likely to continue to be important tools for screening and development of new candidates with improved pharmacological properties. Here, we describe a natural history study to characterize the time course and order of progression of the disease manifestations of EVD in rhesus monkeys. In 12 rhesus monkeys exposed by the intramuscular route to 1000 plaque-forming units of EBOV, multiple endpoints were monitored for 28 days following exposure. The disease progressed rapidly with mortality events occurring 7–10 days after exposure. Key disease manifestations observed consistently across the infected animals included, but were not limited to, viremia, fever, systemic inflammation, coagulopathy, lymphocytolysis, renal tubular necrosis with mineralization, and hepatocellular degeneration and necrosis.

Distinct transcriptional responses to fatal Ebola virus infection in cynomolgus and rhesus macaques suggest species-specific immune responses

“…Additionally, genes relating to coagulation and hypoxia were upregulated to a greater extent in this species (e.g., ADAM8, TREML1, FCGER1). These transcriptional findings are consistent with exaggerated coagulopathy and hepatocellular damage (e.g., more severe loss of platelets and higher levels of AST) in rhesus compared to cynomolgus macaques reported in previous studies [28,29].…”

“…Both species are equally susceptible to EBOV infection; however, differences in the duration/severity of EVD and histopathological presentation exist. Importantly, time to euthanasia following infection with a lethal dose of EBOV-Mayinga or EBOV-Makona is shorter in cynomolgus macaques (5-6 days) compared to rhesus macaques (~8 days) [26][27][28][29]. This is accompanied by earlier changes in inflammatory mediators, earlier onset of viremia and greater severity of cellular stress and coagulopathy (e.g., elevated BUN, CRE, and AST; reduced PLT) in rhesus macaques [26][27][28][29].…”

“…Importantly, time to euthanasia following infection with a lethal dose of EBOV-Mayinga or EBOV-Makona is shorter in cynomolgus macaques (5-6 days) compared to rhesus macaques (~8 days) [26][27][28][29]. This is accompanied by earlier changes in inflammatory mediators, earlier onset of viremia and greater severity of cellular stress and coagulopathy (e.g., elevated BUN, CRE, and AST; reduced PLT) in rhesus macaques [26][27][28][29]. Interestingly, viral titers in lymphoid organs at the time of euthanasia are comparable between the two species despite the delayed viremia [26,27].…”

Kikwit Ebola Virus Disease Progression in the Rhesus Monkey Animal Model

“…EVD progression in animals on this study was similar to previously reported studies [ 21 , 22 , 23 ]. The first indication of infection was detection of the viral NP gene in blood at two days post-exposure (summary in Figure 4 ).…”

Pathogenicity and Virulence of Ebolaviruses with Species- and Variant-specificity

“…Among them, NHPs are considered the "gold standard" animal model since they are highly susceptible to the infection of wild-type EBOV (WT-EBOV) that have been isolated from human samples. Nearly all clinical and pathological features of severe/fatal EVD in humans can be recapitulated in NHPs, including high viremia, strong cytokine/chemokine response, coagulopathy, rash, and hemorrhagic signs [71][72][73][74][75]. Cynomolgus and rhesus macaques have been the most commonly used NHPs for EBOV infection; disease progression in cynomolgus macaques after EBOV infection is slightly faster than that in rhesus macaques [6].…”